Excessive oxidative stress in
cancer cells can induce
cancer cell death. Anticancer activity and drug resistance of
chemotherapy are closely related to the redox state of
tumor cells. Herein, five lipophilic Pt(IV)
prodrugs were synthesized on the basis of the most widely used anticancer drug
cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of
cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary
ovarian cancer cells have been selected to screen those
prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV)
prodrugs, we then synthesized a
polymer with a diselenium bond in the main chain for encapsulating the most effective
prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with
cisplatin. In addition, genome-wide analysis via
RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and
cisplatin. Thereafter, patient-derived xenograft models of hepatic
carcinoma (PDXHCC) and multidrug-resistant
lung cancer (PDXMDR) were established to evaluate the
therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of
platinum-based
cancer therapy.